12-123622674-A-G

Variant names:

• chr12-123622674-A-G
• rs863225052
• NM_001414.4:c.715T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM5

The NM_001414.4(EIF2B1):​c.715T>C​(p.Phe239Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F239V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EIF2B1 NM_001414.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.30
• Publications: 1 publications found

Genes affected

EIF2B1 (HGNC:3257): (eukaryotic translation initiation factor 2B subunit alpha) This gene encodes one of five subunits of eukaryotic translation initiation factor 2B (EIF2B), a GTP exchange factor for eukaryotic initiation factor 2 and an essential regulator for protein synthesis. Mutations in this gene and the genes encoding other EIF2B subunits have been associated with leukoencephalopathy with vanishing white matter. [provided by RefSeq, Oct 2009]

EIF2B1 Gene-Disease associations (from GenCC):

• leukoencephalopathy with vanishing white matter 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• leukoencephalopathy with vanishing white matter

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• ovarioleukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-123622674-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 217282.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	NM_001414.4	MANE Select	c.715T>C	p.Phe239Leu	missense	Exon 8 of 9	NP_001405.1	Q14232-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF2B1	ENST00000424014.7	TSL:1 MANE Select	c.715T>C	p.Phe239Leu	missense	Exon 8 of 9	ENSP00000416250.2	Q14232-1
	EIF2B1	ENST00000929734.1		c.835T>C	p.Phe279Leu	missense	Exon 9 of 10	ENSP00000599793.1
	EIF2B1	ENST00000857210.1		c.751T>C	p.Phe251Leu	missense	Exon 9 of 10	ENSP00000527269.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		9.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.86	P
Vest4		0.57
MutPred		0.50		Gain of catalytic residue at F235 (P = 0.0305)
MVP		0.98
MPC		0.70
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.91
gMVP		0.91
Mutation Taster		=13/87	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs863225052; hg19: chr12-124107221;